A problem with the administration of many pharmaceutical compounds and diagnostic compounds has been the need to retain sufficient quantities of these compounds in contact with the target tissues for a period of time sufficient to accomplish the therapeutic or diagnostic purpose. This problem is particularly acute in connection with compounds administered to the eye. In the ocular environment, tear turnover and drainage through the lacrimal system quickly remove a major portion of any compound administered directly to the eye so that only a small fraction of the original dosage remains in the eye for an extended period of time. In order to keep the pharmaceutical compound present at a therapeutic level, repeated administrations of fairly large doses are required to compensate for the loss from tear turnover and drainage. Similar problems are also encountered in connection with the nasal mucosa, oral cavity and similar physiological environments.
Early approaches to the solution of the problems associated with ocular drug delivery systems utilized semi-solid ointments or gels applied directly to the conjunctiva or cul-de-sac of the eye to retain the pharmaceutical agents contained therein on the ocular surface. Though reasonably effective at retaining adequate drug dosages in contact with the surface of the eye, a major disadvantage associated with ointments and gels is the difficulty in delivering controlled amounts. Many patients experience difficulty in applying the appropriate amount of the ointment or gel to the eye. Additionally, many of the ointments and gels cause unpleasant side effects including blurred vision and the formation of crusts around the eye and on the eyelids.
Another problem associated with the use of semi-solid gels and ointments is the tendency for many of these delivery systems to migrate within the cul-de-sac or fall completely from the eye. While some delivery systems are based upon gels which adhere to mucosa and thus have superior retention properties, many other gel systems do not meet with patient approval because of the discomfort associated with their migration.
Still another problem with many conventional gel and ointment drug delivery systems is the persistence of the gel or ointment within the ocular environment. Long after the available pharmaceutical compound is delivered, the gel or ointment can remain in the eye and continues to cause many unpleasant side effects including crusting and blurred vision. This problem is alleviated by gel drug delivery systems based on erodible gels which gradually dissolve or react to form soluble products at the physiological delivery site. However, patient dissatisfaction associated with accurately delivering recommended doses of these gels remains a problem. When attempting to deliver these gels using drop instillable methods, patients frequently apply too little or too much gel.
Another approach to controlled drug delivery is to utilize a drug loaded solid insert of a matrix material which erodes in physiological environments and simultaneously releases the incorporated drug with the erosion. One such solid insert is formulated of copolymers of a carboxylic acid such as the mono-ester of alkylvinylether/maleic acid copolymers. The ratio of acid functionalities to the number of carbon atoms in these copolymers determines the erosion rate and the drug release profile. These solid inserts function well in applications for extended release profiles. However, a significant disadvantage of these solid inserts for applications which do not require weeks or days of drug release time is the low patient acceptance associated with self-administering solid inserts. This is a particularly strong disadvantage when the inserts are intended for insertion in the ocular environment.
Alternatively, it has been proposed to utilize formulations which gel in response to changes in pH as drug delivery vehicles by carefully controlling the pH of a drug mixture, a solution which increases in viscosity upon mixing with aqueous tear fluid. Typically, these formulations are based upon polycarboxylates at concentrations as high as 10% which result in delivery systems having high buffering capacities and extended gelling times. However, these polycarboxylates have adverse effects on the chemical stability of certain pharmaceutical compounds which precludes their use in these delivery systems.
Accordingly, it is an object of the present invention to provide stable, reversibly gelling drug delivery vehicles which can be used to delivery a variety of pharmaceutical compounds to a physiological system.
It is a further object of the present invention to provide a reversibly gelling drug delivery vehicle which rapidly undergoes a viscosity change upon application to a physiological system.
It is a further object of the present invention to provide a reversibly gelling, drop-instillable drug delivery vehicle which will prolong drug contact time for improved bioavailability and sustained drug release.
It is additionally an object of the present invention to provide a delivery vehicle which is self-lubricating for patient comfort, yet which exhibits muco-adhesive properties for adhesion to mucosa.